NAFLD is defined as steatosis (>5–10% of hepatocytes are fatty), which is not due to excess use of alcohol (defined in European and American guidelines as >20 g of alcohol daily for women and >30 g for men), or other conditions as determined by careful family and medical history, and laboratory tests to exclude at least steatosis due to viral and autoimmune causes and iron overload .
NAFLD is usually asymptomatic and most patients have normal transaminases (ALT <30–40UL−1 for men and <20–30UL−1 for women) [2,3], although NAFLD is the commonest cause of incidentally discovered elevated liver function tests  and the most common cause of chronic liver disease  (Figure 19.1). The prevalence of NAFLD depends on the method of diagnosis but is as common as the MetS (metabolic syndrome). The estimated worldwide prevalence is in the range from 15% (China) to 30% (Dallas Heart Study) .
Some patients with NAFLD have NASH, which is characterized in addition to steatosis by ballooning necrosis in the vicinity of steatotic hepatocytes, mild inflammation, and possibly fibrosis . NASH can only be diagnosed by a liver biopsy. Recent reviews have estimated the worldwide prevalence of NASH to be 3–6% [6,8]. Although the main cause of excess mortality in NASH is CVD , NASH may progress to cirrhosis and end-stage liver disease. Cirrhosis may occur in ∼5% of patients with NASH (see  for review) (Figure 19.2). NASH is perhaps the most common cause of cryptogenic cirrhosis . It is currently the third most important indication for liver transplantation in the US and the only cause with an increasing incidence . Recent data have shown that NAFLD is the most prevalent cause of HCC  (Figure 19.1), which may occur even without cirrhosis in patients with NAFLD [12,13]. The risk of HCC is increased at least twofold in obesity and type 2 diabetes  and may be especially high in patients with NAFLD, who are carriers of the common variant in PNPLA3 (see later) . Identification of patients at risk for NASH and HCC is a major challenge.
The liver is the site of production of two of the key components of the MetS, fasting serum glucose and very-low density lipoprotein (VLDL), which contains most of the triglycerides present in serum. In subjects with NAFLD, the ability of insulin to normally suppress production of glucose and VLDL is impaired resulting in mild hyperglycemia and hypertriglyceridemia, two key features of the MetS [15,16]. The liver, once fatty, also overproduces other markers of cardiovascular risk such as C-reactive protein (CRP), fibrinogen, and coagulation factors [8,17]. The ensuing chapter is focused on reviewing the pathogenesis of NAFLD mostly based on human studies.
Pathogenesis of NAFLD
Sources of intrahepatocellular triglycerides
The hallmark of NAFLD is steatosis, that is, accumulation of triglycerides within hepatocytes. The fatty acids in these triglycerides can be derived from peripheral lipolysis, that is, fatty acids released from adipose tissue, de novo synthesis of fatty acids from simple sugars such as glucose and fructose as well as from amino acids via the pathway of de novo lipogenesis (DNL), or from dietary fatty acids, which can reach the liver via the spillover pathway and through uptake of intestinally derived chylomicron remnants  (Figure 19.3). Spillover is defined as the amount of free fatty acids (FFA) that are released from triglycerides during intravascular lipolysis but not taken up by adipose or muscle tissues. Studies using stable isotopes in humans have suggested that after an overnight fast and during the night, lipolysis provides approximately half of the fatty acids stored in intrahepatocellular triglycerides .The contribution of lipoplysis to intrahepatocellular triglycerides does not appear to be increased if weight-matched subjects with and without increased liver fat content due to NAFLD are compared . Despite this, multiple studies have shown adipose tissue lipolysis to be increased in subjects with NAFLD [20,21]. The pathway, which seems most abnormal in NAFLD is DNL . During a meal, the contribution of lipolysis decreases while that of dietary fatty acids increases . Another mechanism by which triglycerides can accumulate is defective lipolysis within hepatocytes. A major form of NAFLD due to genetic variation in PNPLA3 has recently been identified. The I148M variant in PNPLA3 may impede breakdown of intrahepatocellular triglycerides. This cause of NAFLD as well as others and the mechanisms by which they contribute to NAFLD are discussed later.